1. Field of Invention
Not applicable
2. Description of Related Art
The compound 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole is a synthetic aminobenzothiazole derivative whose (6S) enantiomer, commonly known as pramipexole and commercially available under the Mirapex® name, is a potent dopamine agonist, and thus, mimics the effects of the neurotransmitter dopamine. Pramipexole has also been shown to have both neuroprotective and dopaminergic activities, presumably through inhibition of lipid peroxidation, normalization of mitochondrial metabolism and/or detoxification of oxygen radicals. Therefore, pramipexole may have utility as an inhibitor of the cell death cascades and loss of cell viability observed in neurodegenerative diseases and is indicated for treating Parkinson's disease, cluster headaches, restless legs syndrome and bipolar disorder with only small daily doses required and tolerated by patients activates dopamine receptors. Additionally, oxidative stress may be caused by an increase in oxygen and other free radicals, and has been associated with the fatal neurodegenerative disorder amyotrophic lateral sclerosis (ALS). ALS is a progressive neurodegenerative disorder involving the motor neurons of the cortex, brain stem, and spinal cord. About 10% of all ALS patients are familial cases, of which 20% have mutations in the superoxide dismutase 1 (SOD-1) gene. The SOD-1 enzyme may play a pivotal role in the pathogenesis and progression of familial amyotrophic lateral sclerosis (FALS). Recent studies also link the premature neuronal death associated with ALS to mutated mitochondrial genes which lead to abnormalities in functioning of the energy production pathways in mitochondria.
The neuroprotectant activity of both enantiomers of pramipexole have typical therapeutic doses expected to be in the range of about 10 mg/day to about 1,500 mg/day. However, the pramipexole's agonistic effect on of the D2 family of dopamine receptors only requires therapeutic doses that range between 0.5 and 5.0 mg/day, and even these relatively low doses adverse side effects have been reported. For example, the Boehringer Ingelheim product insert for Mirapex® sets the maximally tolerated dose for humans at 4.5 mg/day, and a dose of pramipexole as low as 1.5 mg has been shown to cause somnolence in humans. Single dose toxicity of pramipexole after oral administration has been studied in rodents, dogs, monkeys and humans. In rodents, death occurred at doses of 70-105 mg/kg and above which is equivalent to a human dose of 7-12 mg/kg/ or approximately 500-850 mg for a 70 kg (˜150 lb) individual. In dogs, vomiting occurred at 0.0007 mg/kg and above, while monkeys displayed major excitation at 3.5 mg/kg. In human subjects, an initial single dose of pramipexole of greater than 0.20 mg was not tolerated. All species showed signs of toxicity related to exaggerated pharmacodynamic responses to the pramipexole related to dopaminergic agonism.
Thus, a clinical use of pramipexole as a mitochondria-targeted antioxidant is unlikely, as the high doses needed for the neuroprotective or anti-oxidative/mitochondrial normalization action are not accessible due to high dopamine receptor affinity associated with the (6S) enantiomer. In contrast, (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine is an effective mitochondria-targeted neuroprotectant that exhibits excellent anti-oxidative properties when administered without adverse side effects. Thus, higher doses of (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine can be tolerated by patients and will allow greater brain, spinal cord and mitochondrial concentrations increasing the degree to which oxidative stress and/or mitochondrial dysfunction may be reduced. The neuroprotective effect of the compositions of this disclosure may also be derived at least in part from the ability of the (6R) enantiomer of pramipexole to prevent neural cell death by at least one of three mechanisms. First, the (6R) enantiomer of pramipexole may be capable of reducing the formation of reactive oxygen species in cells with impaired mitochondrial energy production. Second, the (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine may partially restore the reduced mitochondrial membrane potential that is correlated with Alzheimer's, Parkinson's, Huntington's and amyotrophic lateral sclerosis diseases. Third, the (6R) enantiomer of pramipexole may block the apoptotic cell death pathways which are produced by pharmacological models of Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis diseases and mitochondrial impairment. High doses of (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine required to elicit these neuroprotective effects generally require highly pure preparations of (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine which take into account the upper limit of (6S)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine contamination (0.5 mg to 5.0 mg).
Processes for the preparation of 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole using a simple alkylation reaction were first described in U.S. Pat. Nos. 4,843,086 and 4,886,812. Other preparations of 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole have been described that involve reductive amination rather than simple alkylation and, thus, produce a mixture of the R and S optical isomers with no direct means for further purification of the optical isomers. These known processes for the production of 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole are expensive, labor intensive, and utilize hydride reducing agents that pose safety risks. Furthermore, there are currently no known processes for the direct synthesis of the pure (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine from a diamine. Therefore, the R isomer must be synthesized as a mixture of the optical isomers that is purified by expensive and time consuming methods that may utilize other problematic substances. Moreover, known processes involving deamination result in a loss of enantiomeric purity, and methods useful for resolution of the optical isomers from mixtures fall short of producing chirally and chemically pure preparations of the R enantiomer or the S enantiomer.